This proposal is an R21 in response to RFA-MH-12-071: Pathophysiology of HIV-Associated Neurodegeneration in Aging Populations on Long-Term Anti-Retroviral Therapy. Highly Active Anti- Retroviral Therapy (HAART) has led to a dramatic decrease in the incidence and prevalence of HIV- associated dementia, but most studies suggest that the prevalence of less severe forms of cognitive impairment ranges from 15 to 50%. Some forms of HAART exacerbate vascular disease and several reports suggest a link between vascular disease and cognition. The mechanism by which vascular disease affects cognition is not known but this work will test the hypothesis that vascular dysfunction leads to changes in mean diffusivity (MD) as detected on diffusion tensor MRI (DTI) images. These changes in MD reflect axon and/or myelin dysfunction that result in slowing of information transfer and cognitive impairment. Whereas most studies looking at the association of vascular disease and cognition focus on the extracranial carotid artery, the proposed study also includes measures of intracranial large vessels as well as small vessels. A sample of 84 women from the Brooklyn site of the Women's Interagency Study (WIHS) will be evaluated with 4 measures of vascular health (carotid ultrasound, transcranial color dopplers (TCCD), magnetic resonance angiography, and quantitative digital retinal photography (QRP)). 3 T MRI scans will be obtained at New York University that will be analyzed by Dr. Glenn Stebbins at Rush University. These data will be combined with neuropsychological data collected every two years on all WIHS participants to accomplish the following aims: 1) Test the relationships between vascular health and quantitative brain MRI measures including DTI and assess the effects of age, HIV, and HAART on these relationships; 2) Assess the relationships between vascular measure and quantitative MRI measures with cognition and determine how HIV, age, and HAART influence these relationships; and 3) Test the effects of HIV, age, and HAART on brain vascular health. Although this is a high risk proposal, it is also high reward because if successful it will providea mechanism for some aspects of cognitive impairment in HIV (as well as in older persons without HIV) and provide multiple targets for intervention. If small vessel disease is worsened with certain HAART regimens, it could lead to relatively rapid changes in treatment protocols. Because this work is high risk and high reward, a relatively small sample will be evaluated to determine whether to go forward with a larger study. PUBLIC HEALTH RELEVANCE: There are concerns that antiretroviral therapy (ARV) for HIV, while life saving, may be associated with serious side effects including actually worsening cognitive function. This project tests whether brain vascular disease associated with aging, and possibly HIV and/or ARV, is associated with brain changes detectable on special MRI sequences and with cognitive changes. Results from this research may lead to modifications in ARV for HIV and as well may help understand one of the causes of cognitive change in older persons without HIV.